The long term objective of the Program Project Grant Diabetes in Pregnancy III, is to decrease maternal & mortality in diabetic pregnancy. The major theses is that maternal glucose control & reduction of fetal hyperinsulinism reduce metabolic & functional disturbances in mother & fetus. Section A Drs. Miodovnik, Berk, Ballard, Dignan, & Tsong conduct a core clinical trial: continuing a unique prospective randomized trial of strict glycemic control vs less strict control, beginning in the first 9 weeks vs late entry, & a control group. The thesis is: strict early control reduces maternal complications, early fetal loss, malformations, & neonatal morbidity & mortality. A 1) Drs. Berk & Miodovnik test the thesis: impaired adrenergic conterregulatory response to hypoglycemic increases frequency & severity of hypoglycemia in pregnancy; strict glycemic control results in frequent & severe hypoglycemia & impaired adrenergic counferregulation. A2) Drs. Sperling, Mimouni & Compaigne test the thesis: hyperplastic fetal islets results in long term insulin hyperresponsiveness to secretagogues including glucose; & persistent hyperinsulinemic responsiveness induces insulin resistance. A3) Drs. Mimouni, Tsang & Ross test the thesis: maternal diabetic magnesium deficiency may result in neon(ital hypoporathyroidism, magnesium administration in infants results in higher magnesium, parathyroid & calcium, but similar 1,25(OH)2 D. A4) Drs. Berk & Lipman will study the short & long-term consequences of pregnancy on diabetic microvascular complications. Section B Dr. Richardus Ross directs a core alloxan diabetic pregnant sheep model. B1) Drs. Ross, Mimouni & Tsong test the thesis that maternal 1,25-vitamin D production is impaired in diabetic pregnancy, leads to decreases in intestinal calcium absorption, bone turnover & placental calcium transfer. Adaptive fetal responses include enhanced 1,25-vitamin D production & decreased bone mineralization. B2) Drs. Whitsett & Korfhagen test the thesis: insulin dependent inhibition of the SP-B gene is cis-active & maps in or near the SAP gene promoter: Clinical sheep studies of SPA & SP-B expression in IDM will provide in vivo correlates of molecular studies. B3) Dr. Cuppoletti tests the thesis: insulin in the fetus: increases glucose transport protein complement & glucose transport in isolated cardiac myocytes; & "triggers" synthesis of MRNA for new D-glucose carrier proteins. B4) Dr. Sperling will apply the Fick principle & isotope dilution in-normal & diabetic pregnant sheep with catheterized fetal, utero-placental & maternal circulations comparing glucose, fructose & leucine metabolism & their potential contribution to fetal energy & growth. Section C, Drs. Tsong, Sperling, Campaigne & Ms. Gratton provide administrative organization. CI The Core biostatistics group, Drs. Hertzberg & Buncher provide integrated support for all studies. In this PPG,basic & clinical studies complement each other in an integrated, multidisciplinary study.